title: Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.
abstract: The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Kerry N
authors.initials: KN
authors.lastname: Veth
authors.forename: Jason R
authors.initials: JR
authors.lastname: Willer
authors.forename: Ross F
authors.initials: RF
authors.lastname: Collery
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Gray
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Willer
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wagner
authors.forename: Mary C
authors.initials: MC
authors.lastname: Mullins
authors.forename: Ava J
authors.initials: AJ
authors.lastname: Udvadia
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
authors.forename: Brian A
authors.initials: BA
authors.lastname: Link
mesh_terms: D000375:Aging / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000473:pathology; D001483:Base Sequence; D002452:Cell Count; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005123:Eye / Q000473:pathology*; D005901:Glaucoma / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D006871:Hydrophthalmos / Q000150:complications; D007429:Intraocular Pressure; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009216:Myopia / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D009898:Optic Disk / Q000473:pathology / Q000648:ultrastructure; D009929:Organ Size; D010641:Phenotype; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D013312:Stress, Physiological / Q000235:genetics; D015854:Up-Regulation; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D029961:Zebrafish Proteins